EP0514130A2 - Glycoprotéine acide d'os (BAG-75) pour l'inhibition de la résorption osseuse - Google Patents

Glycoprotéine acide d'os (BAG-75) pour l'inhibition de la résorption osseuse Download PDF

Info

Publication number
EP0514130A2
EP0514130A2 EP92304260A EP92304260A EP0514130A2 EP 0514130 A2 EP0514130 A2 EP 0514130A2 EP 92304260 A EP92304260 A EP 92304260A EP 92304260 A EP92304260 A EP 92304260A EP 0514130 A2 EP0514130 A2 EP 0514130A2
Authority
EP
European Patent Office
Prior art keywords
bone
bag
resorption
disease
fragment
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP92304260A
Other languages
German (de)
English (en)
Other versions
EP0514130A3 (en
Inventor
Masahiko Sato
Jeffrey P. Gorski
Gideon A. Rodan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
University of Missouri System
Original Assignee
Merck and Co Inc
University of Missouri System
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck and Co Inc, University of Missouri System filed Critical Merck and Co Inc
Publication of EP0514130A2 publication Critical patent/EP0514130A2/fr
Publication of EP0514130A3 publication Critical patent/EP0514130A3/en
Withdrawn legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to a new method for treating mammals suffering from bone disease associated with increased bone resorption involving the use of a therapeutically effective amount of bone acidic glycoprotein 75, or a 50kDa fragment thereof, containing an N-terminal sequence of: 2. Brief Description of Disclosure in the Art
  • osteoporosis hypercalcemia of malignancy
  • osteopenia due to bone metastases
  • periodontal disease hyperparathyroidism
  • periarticular erosions in rheumatoid arthritis Paget's disease
  • immobilization-induced osteopenia and glucocorticoid treatment.
  • All these conditions are characterized by bone loss, resulting from an imbalance between bone resorption (breakdown) and bone formation, which continues throughout life at the rate of about 14% per year on the average.
  • the rate of bone turnover differs from site to site, for example it is higher in the trabecular bone of the vertebrae and the alveolar bone in the jaws than in the cortices of the long bones.
  • the potential for bone loss is directly related to turnover and can amount to over 5% per year in vertebrae immediately following menopause, a condition which leads to increased fracture risk.
  • Bone acidic glycoprotein 75 (BAG 75) is a new 75kDa naturally occuring glycoprotein known in the art and its properties and preparation are described by J.P. Gorski et al. in J. Biological Chemistry, vol. 265, pp. 14956-14963 (1990) and ibid., vol. 263, pp. 15938-15945 (1988).
  • BAG 75 is a phosphorylated glycoprotein from the mineralized compartment of rat calvarial (skull) tissue with a limited homology to the matrix protein osteopontin (2ar, pp69, Sppl, OP) , is antigenically distinct, predominantly localized to calcified tissues, and represents a major product of osteoblasts (cells involved with bone formation) and may be able to undergo a characteristic fragmentation in vivo and in vitro.
  • BAG 75 purified from bone
  • BAG 75/bone complex is effective in complexing with mammalian bone to inhibit the action of osteoclasts in causing bone resorption (dissolution).
  • the inhibition is primarily caused by the formation of a BAG 75/bone complex rather than inhibitions between osteoclasts and free BAG 75 in the biological media.
  • BAG 75 and the 50kDa fragment are potent inhibitors of bone resorption; BAG 75 impedes (modulates) osteoclastic interaction with bone; it is the BAG 75/bone complex that inhibits bone resorption, not interaction between osteoclasts and BAG 75 free in the biological media; and because BAG 75 is a natural bone protein, it can have important physiological advantages over synthetic inhibitors of bone resorption.
  • a process for treating mammals suffering from a bone condition caused or mediated by increased bone resorption comprising the step of administering to said mammals a therapeutically effective amount of bone acidic glycoprotein 75, containing the N-terminal sequence of:
  • Mammalian bone is composed of cells, hydroxyapatite, collagen, blood vessels, nerves and non-collagenous matrix proteins.
  • non-collagenous proteins which include osteopontin, bone sialoprotein, osteocalcin and os- teonectin, have been shown to be involved in the osteoblastic mediated processes for bone formation.
  • BAG 75 was extracted from rat calvaria and purified by ion exchange and hydroxyapatite chromatographic steps. As reported in the literature, the protein has a molecular weight of 75,000, i.e. 75 kDa, as determined by SDS-PAGE, contains 29.32 molar content of acidic amino acid residues, a 7.0% (w/w) content of sialic acid and a 7.9% molar content of organic phosphate.
  • the N-terminal sequence does not show any sequence homology with the primary structure of human bone sialoprotein and does not bind anti-bone sialoprotein antibodies.
  • The-N-terminal sequence of bone acidic glycoprotein-75 is unique, however, and a 33% homology is shared with the rat matrix protein osteopontin over the first 15 residues.
  • Some affinity-purified antibodies against osteopontin can cross-react to bone acidic glycoprotein-75 and to bone sialoprotein upon immunoblotting, however this result is likely due to impurities of BAG-75 and bone sialoprotein in osteopontin preparations used for immunization and to prepare immunoaffinity adsorbents.
  • Antibodies directed against N-terminal residues 3-13 of BAG-75 or against the protein as a whole are specific and do not crossreact with bone sialoprotein, osteopontin, or other proteins from bone whether as purified proteins or as components of crude calvarial extracts.
  • bone acidic glycoprotein-75 is a new phosphorylated glycoprotein from the mineralized compartment of rat calvarial tissue with a limited structural homology to osteopontin.
  • the known 50kDa fragment described above by Gorski, et al., can be formed by splitting the 75kDa glycoprotein by long-term storage or by proteolysis with stromelysin.
  • BAG 75 or the 50kDa glycoprotein are used to inhibit the conditions of bone resorption in mammals needing such treatment, i.e. humans suffering from osteoporosis, Paget's disease, hypercalcemia of malignancy, and the like.
  • the glycoprotein can be delivered to the mammal via a conventional injectable formulation, i.e. saline solution, by a once-a-day dosage regimen, in an amount of about 50 nanomolar per day per person (average 70 Kg weight).
  • a conventional injectable formulation i.e. saline solution
  • a once-a-day dosage regimen in an amount of about 50 nanomolar per day per person (average 70 Kg weight).
  • BAG 75 purified from rat calvaria can be obtained as described in the articles above by J. Gorski (Univ. Missouri).
  • the 50kDa fragment can also be obtained from BAG 75 by fragmentation, i.e. with stromelysin, as described by Gorski above.
  • the chicken osteoclast bone resorption assay is described as follows:
  • Osteoclasts were isolated from chickens by methods described in Blair et al. (J. Cell Biol 102:1164, 1986). Medullary bone was harvested from split femora and tibiae of Dekalb XL laying hens maintained on a Ca ++ deficient diet (5070C-9, Purina Mills Inc., St. Louis, MO) for 2-4 wk. The bone suspension was washed in PBS at 4°C, pressed through a 110 ⁇ m nylon mesh, incubated in 0.2% NaCi for 2 minutes at 37°C to lyse red blood cells, and then sedimented through a 70% serum gradient for 90 minutes at 4°C.
  • Ca ++ deficient diet 5070C-9, Purina Mills Inc., St. Louis, MO
  • the bottom 5 ml was resuspended over a 3 step Nycodenz gradient (1.073, 1.099, 1.143 g/cm 3 ) (Accurate Chemical & Scientific Corp., Westbury, NY) and centrifuged at 350 g for 20 minutes at 4°C.
  • Cells from below the first band to above the pellet were pooled and resuspended into alpha-MEM, pH 7.0-7.2, 10% fetal calf serum, antibiotics (Gibco Laboratories, Grand Island, NY) plus 2-5 ⁇ g/ml cytosine-1-B-D-arabinofuranoside at 4°C.
  • the cell suspension was aliquoted into Costar plates (Cambridge, MA) to yield 1000-4000 osteoclasts/cm 2 .
  • Bone resorption was assayed by measuring the [ 3 H] released from labelled bone particles aliquoted at 100 wg/cm 2 onto chicken osteoclasts in 48 well plates (Costar Corp.). Bone particles (20-53 ⁇ m) were made by seiv- ing crushed bone from rats injected with [ 3 H] proline (Amersham Corp., Arlington Hts., IL) by the known art procedure as described by Blair, et al. J. Cell Biol. 102:1164 (1986). [ 3 H] released into the media was quantitated with a liquid scintillation counter (LKB Instruments, Inc., Gaitherburg, MD). Resorption was typically assayed between days 4-6 in culture.
  • Figure 1 shows the resulting effects of rat bone acidic glycoprotein 75 (BAG 75) on the bone resorption activity of isolated chicken osteoclasts.
  • BAG 75 rat bone acidic glycoprotein 75
  • Figure 1 shows the resulting effects of rat bone acidic glycoprotein 75 (BAG 75) on the bone resorption activity of isolated chicken osteoclasts.
  • the effect of rat BAG 75 on resorption was plotted with the effect of other noncollagenous bone proteins on resorption, including rat osteopontin, human vitronectin, human fibronectin, rat bone sialoprotein, and the 50kDa fragment of rat BAG 75, as determined by this same assay.
  • the reason for comparing BAG 75 to osteopontin, vitronectin, fibronectin, and BSP2 was to examine the possibility that BAG 75, as well as the others, may mediate cell interactions to bone, which is clearly affirmed by the data.
  • transient incubation of osteoclasts with BAG 75 had no effect (did not inhibit) resorption.
  • transient incubation of bones with BAG 75 resulted in significant (40%) inhibition of resorption.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Nutrition Science (AREA)
  • Marine Sciences & Fisheries (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
EP19920304260 1991-05-13 1992-05-12 Bone acidic glycoprotein (bag-75) for inhibiting bone resorption Withdrawn EP0514130A3 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US69909291A 1991-05-13 1991-05-13
US699092 1991-05-13

Publications (2)

Publication Number Publication Date
EP0514130A2 true EP0514130A2 (fr) 1992-11-19
EP0514130A3 EP0514130A3 (en) 1993-07-21

Family

ID=24807893

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19920304260 Withdrawn EP0514130A3 (en) 1991-05-13 1992-05-12 Bone acidic glycoprotein (bag-75) for inhibiting bone resorption

Country Status (3)

Country Link
EP (1) EP0514130A3 (fr)
JP (1) JPH05148300A (fr)
CA (1) CA2068389A1 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5674844A (en) * 1991-03-11 1997-10-07 Creative Biomolecules, Inc. Treatment to prevent loss of and/or increase bone mass in metabolic bone diseases
WO1998028423A2 (fr) * 1996-12-20 1998-07-02 Board Of Regents, The University Of Texas System Compositions et procedes d'utilisation des facteurs inhibant les osteoclastes
US6693175B2 (en) 1997-09-24 2004-02-17 Sankyo Co., Ltd. Method for diagnosing bone dysbolism
US6855808B2 (en) 1995-02-20 2005-02-15 Sankyo Co., Ltd. Proteins and methods for producing the proteins
US6919434B1 (en) 1995-02-20 2005-07-19 Sankyo Co., Ltd. Monoclonal antibodies that bind OCIF
US7056882B2 (en) 1991-03-11 2006-06-06 Curis, Inc. Treatment to prevent loss of and/or increase bone mass in metabolic bone diseases
US7192718B2 (en) 1997-04-15 2007-03-20 Sankyo Co. Ltd Methods for identifying a substance which specifically binds to an osteoclastogenesis inhibitory factor-binding molecule and modulates the biological activity thereof
US7411050B2 (en) 1996-12-23 2008-08-12 Immunex Corporation Monoclonal blocking antibody to human RANKL
US7718776B2 (en) 2002-04-05 2010-05-18 Amgen Inc. Human anti-OPGL neutralizing antibodies as selective OPGL pathway inhibitors
US7807795B2 (en) 1997-04-16 2010-10-05 Amgen Inc. Antibodies to osteoprotegerin binding proteins
US7923008B2 (en) 1997-04-16 2011-04-12 Amgen Inc. Methods for decreasing osteoclast formation or bone resorption using an antibody to osteoprotegerin binding protein
EP2332974A3 (fr) * 1995-12-22 2012-01-11 Amgen, Inc Ostéoprotégérine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
THE JOURNAL OF BIOLOGICAL CHEMISTRY vol. 263, no. 31, 1988, BALTIMORE,USA pages 15938 - 15945 GORSKI ET AL 'ISOLATION OF NEW PHOSPHORYLATED GLYCOPROTEIN FROM MINERALIZED PHASE OF BONE THAT EXHIBITS LIMITED HOMOLOGY TO ADHESIVE PROTEIN OSTEOPONTIN' *
THE JOURNAL OF BIOLOGICAL CHEMISTRY vol. 265, no. 25, 1990, BALTIMORE,USA pages 14956 - 14963 GORSKI ET AL 'BONE ACIDIC GLYCOPROTEIN-75 IS A MAJOR SYNTHETIC PRODUCT OF OSTEOBLASTIC CELLS AND LOCALIZED AS 75 AND/OR 50-KDA FORMS IN MINERALIZED PHASES OF BONE AND GROWTH PLATE AND IN SERUM' *

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7056882B2 (en) 1991-03-11 2006-06-06 Curis, Inc. Treatment to prevent loss of and/or increase bone mass in metabolic bone diseases
US5674844A (en) * 1991-03-11 1997-10-07 Creative Biomolecules, Inc. Treatment to prevent loss of and/or increase bone mass in metabolic bone diseases
US7125686B1 (en) 1995-02-20 2006-10-24 Sankyo Co., Ltd. Proteins and methods for producing the proteins
US7205397B2 (en) 1995-02-20 2007-04-17 Sankyo, Co., Ltd. Proteins and methods for producing the proteins
US6855808B2 (en) 1995-02-20 2005-02-15 Sankyo Co., Ltd. Proteins and methods for producing the proteins
US6919434B1 (en) 1995-02-20 2005-07-19 Sankyo Co., Ltd. Monoclonal antibodies that bind OCIF
US7468268B2 (en) 1995-02-20 2008-12-23 Daiichi Sankyo Co., Ltd. Nucleic acid molecules encoding osteoclastogenesis inhibitory factor proteins
US7276344B2 (en) 1995-02-20 2007-10-02 Sankyo Co., Ltd. Methods for using the osteoclastogenesis inhibitory factor (OCIF) protein
EP2332974A3 (fr) * 1995-12-22 2012-01-11 Amgen, Inc Ostéoprotégérine
WO1998028423A3 (fr) * 1996-12-20 1998-09-03 Univ Texas Compositions et procedes d'utilisation des facteurs inhibant les osteoclastes
WO1998028423A2 (fr) * 1996-12-20 1998-07-02 Board Of Regents, The University Of Texas System Compositions et procedes d'utilisation des facteurs inhibant les osteoclastes
US7932375B2 (en) 1996-12-23 2011-04-26 Immunex Corporation Kits for detecting rank nucleic acids
US7411050B2 (en) 1996-12-23 2008-08-12 Immunex Corporation Monoclonal blocking antibody to human RANKL
US8715683B2 (en) 1996-12-23 2014-05-06 Immunex Corporation RANK ligand polypeptides
US8377690B2 (en) 1996-12-23 2013-02-19 Immunex Corporation Cells and methods for producing blocking antibodies to human RANKL
US7744886B2 (en) 1996-12-23 2010-06-29 Immunex Corporation Methods for interfering with rank signaling
US7192718B2 (en) 1997-04-15 2007-03-20 Sankyo Co. Ltd Methods for identifying a substance which specifically binds to an osteoclastogenesis inhibitory factor-binding molecule and modulates the biological activity thereof
US7449185B2 (en) 1997-04-15 2008-11-11 Daiichi Sankyo Company, Limited Antibodies to OCIF-binding molecules
US7527790B2 (en) 1997-04-15 2009-05-05 Daiichi Sankyo Company, Limited Methods of reducing bone absorption comprising administering an antibody that binds OBM
US7807795B2 (en) 1997-04-16 2010-10-05 Amgen Inc. Antibodies to osteoprotegerin binding proteins
US7923008B2 (en) 1997-04-16 2011-04-12 Amgen Inc. Methods for decreasing osteoclast formation or bone resorption using an antibody to osteoprotegerin binding protein
US6998242B2 (en) 1997-09-24 2006-02-14 Sankyo Co., Ltd. Method of diagnosing metabolic bone diseases
US6693175B2 (en) 1997-09-24 2004-02-17 Sankyo Co., Ltd. Method for diagnosing bone dysbolism
US7718776B2 (en) 2002-04-05 2010-05-18 Amgen Inc. Human anti-OPGL neutralizing antibodies as selective OPGL pathway inhibitors
US8367063B2 (en) 2002-04-05 2013-02-05 Amgen, Inc. Human anti-OPGL neutralizing antibodies as selective OPGL pathway inhibitors
US8455629B2 (en) 2002-04-05 2013-06-04 Amgen Inc. Human anti-OPGL neutralizing antibodies as selective OPGL pathway inhibitors

Also Published As

Publication number Publication date
EP0514130A3 (en) 1993-07-21
CA2068389A1 (fr) 1992-11-14
JPH05148300A (ja) 1993-06-15

Similar Documents

Publication Publication Date Title
JP3053116B2 (ja) 医薬組成物
Åkesson et al. Impairment of bone turnover in elderly women with hip fracture
JP3686335B2 (ja) 骨および軟骨成長と修復を促進する方法
US6165514A (en) Methods of enhancing repair, healing and augmentation of tissues and organs
EP0514130A2 (fr) Glycoprotéine acide d'os (BAG-75) pour l'inhibition de la résorption osseuse
Kawaguchi et al. Local application of recombinant human fibroblast growth factor‐2 on bone repair: A dose–escalation prospective trial on patients with osteotomy
EP0289314B1 (fr) Emploi de IGF-II pour le traitement de désordres des os
Rüegsegger et al. Comparison of the treatment effects of ossein-hydroxyapatite compound and calcium carbonate in osteoporotic females
CA2159449C (fr) Composition a base de pdgf et de vitamine d stimulant la croissance d'osteoblastes
JPH09501186A (ja) コレステリルエステル運搬蛋白質阻害ペプチドおよびこれを含む動脈硬化症のための予防および治療剤
Ushiroyama et al. Efficacy of ipriflavone and 1α vitamin D therapy for the cessation of vertebral bone loss
Bail et al. The effect of growth hormone on insulin-like growth factor I and bone metabolism in distraction osteogenesis
Groessner-Schreiber et al. Osteoclast recruitment in response to human bone matrix is age related
US20080176787A1 (en) Parathyroid hormone analogues and methods of use
DE69029415T2 (de) Osteogenische Wachstumfaktoren, die aus sich regenerierendem Knochenmark identifiziert werden
WO1996036349A1 (fr) ACTIVATION POST-TRANSLATIVE DU FACTEUR DE CROISSANCE TRANSFORMANT BETA1 (TGFβ1) FAISANT INTERVENIR LE RECEPTEUR CD36 DU TSP-1
EP1755637B1 (fr) Methodes destinees a prevenir ou traiter des maladies osseuses
EP2056862A2 (fr) Analogues de l'hormone parathyroïdienne et leurs procédés d'utilisation
Cellini et al. Epidermal growth factor in the topical treatment of herpetic corneal ulcers
US20220275025A1 (en) Bone remodeling regulatory peptides and application thereof
JP4939715B2 (ja) 骨合成代謝活性物質として金属プロテイナーゼ−２（ｔｉｍｐ−２）の組織阻害剤を含む薬剤
Culler Inhibin suppresses luteinizing hormone (LH)-releasing hormone self-priming: direct action on follicle-stimulating hormone secretion and opposition of estradiol-enhanced LH secretion.
Hayann et al. A nontoxic strontium nanoparticle that holds the potential to act upon osteocompetent cells: An in vitro and in vivo characterization
US20090042774A1 (en) Parathyroid hormone analogues and methods of use
AU662911B2 (en) Use of beta-cell tropin (ACTH 22-39) antagonists in the treatment of hyperinsulinaemia and associated diseases

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): CH DE FR GB IT LI NL

PUAL Search report despatched

Free format text: ORIGINAL CODE: 0009013

AK Designated contracting states

Kind code of ref document: A3

Designated state(s): CH DE FR GB IT LI NL

17P Request for examination filed

Effective date: 19931208

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

18W Application withdrawn

Withdrawal date: 19941205